The cochlea's sensory cells are connected to the brain by four kinds of nerve fibers: the two sensory pathways, type-I and type-II auditory-nerve fibers, carry separate afferent signals from inner hair cells (IHCs) or outer hair cellls (OHCs), respectively, to the brainstem;two feedback control circuits in the olivocochlear (OC) bundle carry efferent signals from the brainstem back to OHCs and/or afferent neurons. Our recent work has suggested novel functional roles for the two unmyelinated pathways: the enigmatic type-II afferents and the poorly understood lateral (L)OC efferent targeting type-I afferents in the IHC area. We have also discovered a novel peripheral effect of the medial (M) OC efferents and have data suggesting a novel functional role for GABAergic transmiission in the MOC system. Over the next five years, we propose to test these new ideas. In Aim 1, we use surgical de-efferentation, animal behavior, physiology and histopathology in mice and ferrets to test the idea that the two functions of LOC efferents are 1) to balance the neuronal excitability in the two ears to fine-tune the accuracy of sound localization based on interaural level differences and 2) to minimize the acute excitoxicity of acoustic overexposure that would otherwise cause neuronal degeneration. In Aim 2, we use molecular biology and immunohistochemistry in mice to describe patterns of receptor expression in the LOC's target cells (i.e. type-I afferents and IHCs) to dissect the cellular mechanisms underlying effects seen in Aim 1. In Aim 3, we use pharmacology and electrophysiology in both in vitro and in vivo models to test the novel view that type-II afferents 1) mediate intercommunication among OHCs via a local neural network formed by their reciprocal synapses and 2) participate in a control circuit modulating excitability of the MOC reflex in which GABAergic signaling is a key component. In Aim 4, we use pharmacology and mice with targeted deletion of receptor subunits to dissect the mechanisms underlying a novel peripheral effect of MOC efferents (including possible involvement the type-II network studied in Aim 3) and to test the idea that central adrenergic signaling mediates the modulation of MOC reflex strength seen after contralateral cochlear destruction. Completion of these four interconnected aims will signifcantly enhance our understanding of feedback control in the auditory periphery and the functional significance of all the cochlea's fiber pathways. In addition to the basic science they address, these Aims are relevant to problems of noise-induced hearing loss and its interactions with age-related hearing loss, as both feedback pathways are now directly implicated in protecting the ear from acoustic injury. Our studies promise to clarify the underlying mechanisms.